Challenging the FDA Black Box Warning for High Aspirin Dose With Ticagrelor in Patients With Diabetes

Abstract

Ticagrelor, a novel reversible antiplatelet agent, has a Food and Drug Administration (FDA) black box warning to avoid maintenance
doses of aspirin (ASA) >100 mg/daily. This restriction is based on the hypothesis that ASA doses >100 mg somehow decreased
ticagrelor’s benefit in the Platelet Inhibition and Patient Outcomes (PLATO) U.S. cohort. However, these data are highly postrandomized,
come from a very small subgroup in PLATO (57% of patients in the U.S. site), and make no biological sense. Moreover, the ticagrelor-ASA
interaction was not significant by any multivariate Cox regression analyses. The Complete Response Review for ticagrelor indicates
that for U.S. PLATO patients, an ASA dose >300 mg was not a significant interaction for vascular outcomes. In the ticagrelor-ASA
>300 mg cohort, all-cause and vascular mortality were not significantly increased (hazard ratio [HR] 1.27 [95% CI 0.84–1.93],
P = 0.262 and 1.39 [0.87–2.2], P = 0.170), respectively. Furthermore, for major adverse cardiovascular events (MACEs), 30-day all-cause mortality, and 30-day
vascular mortality, the strongest interaction is the diabetes-ASA interaction. That is, patients who had diabetes had significantly
fewer MACEs through study end (0.49 [0.34–0.63], P < 0.0001), significantly less 30-day all-cause mortality (0.33 [0.20–0.56], P < 0.0001), and significantly less 30-day vascular mortality (0.35 [0.22–0.55], P < 0.0001), respectively, when given high-dose (300–325 mg) ASA, regardless of treatment (clopidogrel or ticagrelor) assignment.
The black box warning for the use of maintenance ASA doses >100 mg with ticagrelor is inappropriate for patients with diabetes
and not evidence based.

A post hoc secondary analysis from the PLATO trial was undertaken to suggest that the increased use of ASA 300–325 mg (53.6%)
in the U.S. compared with the rest of the world (1.7%) was the only factor to explain (out of 37 variables explored) the regional
interaction that ticagrelor was less effective and potentially more harmful than clopidogrel (2). However, this interaction was not significant, is highly postrandomized, comes from a very small subgroup of PLATO, and
makes no biological sense (3).

Ticagrelor-ASA hypothesis

The claimed ticagrelor-ASA interaction states that ticagrelor plus low-dose ASA is beneficial, whereas increasing doses of
ASA in combination with ticagrelor produces adverse effects. Ticagrelor, having nearly complete P2Y12 platelet receptor blockade,
does not exhibit the added antiaggregatory benefit derived from ASA, in contrast to what is seen with clopidogrel. Moreover,
it is postulated that the incomplete and variable P2Y12 blockade seen with clopidogrel derives more benefit from ASA with
less display of adverse effects. This hypothesis distinguishes between ASA-mediated effects in platelets versus targeting
endothelial cells in the vessel wall; that is, in platelets, ASA’s inhibition of cyclooxygenase (COX)-1 causes a decrease
in thromboxane A2 formation, inhibiting platelet aggregation. However, at higher doses, ASA also blocks the COX-2– mediated
production of the vasodilator prostacyclin, causing an increase in vascular resistance.

The PLATO sponsor conducted a study in anesthetized dogs in an attempt to show vascular effects secondary to inhibition of
prostacyclin production. The study showed no difference between ticagrelor and ASA compared with clopidogrel and ASA combination
or ASA alone when absolute blood flow was examined. The FDA records indicate that “there is no clear explanation why ASA’s
proposed inhibition of endothelial prostacyclin is able to outweigh ticagrelor’s, but not clopidogrel’s beneficial effects
of thromboxane-A2 inhibition, platelet inhibition, and interactions with phosphodiesterase isoforms” (3). It is entirely unclear why ASA adds to the lower platelet inhibition produced by clopidogrel but not to the greater platelet
inhibition produced by ticagrelor and why ASA’s ability at higher dosages to block COX-2–mediated production of the vasodilator
prostacyclin produces vasoconstriction would only manifest in ticagrelor patients. In short, there is no clear explanation
of why the reduced prostacyclin vasoconstriction should be relevant selectively and exclusively only to ticagrelor. The other
major weakness of this hypothesis is that the platelet aggregation assay results aren’t consistent with the clinical bleeding
rates in PLATO, for which higher ASA dosage is associated with more bleeding and likely a more additive effect upon bleeding
with ticagrelor than with clopidogrel (3).

Ticagrelor-ASA interaction is not significant in PLATO short-term results but other interactions, including diabetes, are

The FDA Complete Response Review states that the most striking PLATO result was the reported long-term mortality benefit of
ticagrelor. PLATO provides much less substantial evidence of short-term benefits and beneficial effects on thrombotic events.
This combination of results is inconsistent with those of all earlier platelet inhibitor ACS trials, which have shown strong
short-term benefits and smaller or no later benefits particularly regarding mortality. The ticagrelor-ASA interaction is not
significant for the short-term results and not significant for mortality results regardless whether short- or long-term. The
short-term results and mortality results demonstrate that three other interactions are more important and creditable than
the ticagrelor-ASA interaction. These interactions are the following:

The FDA transcript summarizes that when applying Cox regressions analyses the interaction term for ticagrelor and region is
insignificant in all regressions. For short-term results there is no major U.S. versus rest of the world discrepancy that
requires explanation. The interaction term for ticagrelor and ASA dosage is insignificant in all regressions. The short-term
results do not support worse outcomes with higher ASA dosage in ticagrelor patients alone.

Ticagrelor-ASA interaction is significant for sponsor’s primary end point but a spurious correlation cannot be ruled out

The Complete Response Review states that the proposed ticagrelor-ASA interaction hypothesis suffers from many problems: the
definition is not obvious, the determination is uncertain in many patients, the interaction is not consistent for various
definitions and for different end points and time points, and the interpretation is flawed. For instance, it is unclear how
the ASA dose has been defined since the mean, median, and the maximum doses were not matched. Another important issue is the
time frame for which the ASA dose was used in the summary statistics, since it differs for the entire trial period: should
the last 10 days, the last dose, or the loading ASA doses be considered? In fact, another statistical problem is the handling
of the missed data. Since there are about a dozen variations to consider and analyze the effects of before choosing one, it
should not be surprising that one, or more, associations may be “significant.” Importantly, the definition of ASA dosage is
completely post hoc and derived after the study was unblinded and analyzed. Besides the definition not being obvious, there
are problems with the PLATO determinations of ASA dosage. The FDA report indicates that some drugs (carbasalate [a calcium
salt of acetylsalicylate used in Europe], anoprin [miscoded to chlorphenamine], and “inj loparin” [enoxaparin]) had been miscoded
to ASA (3).

Finally, there is a converse problem with handling “missing” values. In PLATO, sites recorded concomitant drugs, including
ASA, if the patient received the drug. There was no specific place to record that a drug was not given. Moreover, while examining
the case report forms of patients without ASA records, there was not infrequently a statement recorded justifying why ASA
was not given. These patients also had higher baseline rates of histories of gastrointestinal bleeding and peptic ulcer disease
(3).

Conclusions

The aforementioned data clearly indicate that it is inappropriate to follow a black box warning for ASA dosages >100 mg with
ticagrelor in patients with diabetes. A more plausible argument is that high-dose ASA improves clopidogrel benefit and may
partially explain the disadvantage with ticagrelor versus clopidogrel in the U.S. Patients assigned to high-dose ASA (300–325
mg) in the randomized Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for
Interventions (CURRENT-OASIS 7) trial had a significant reduction in recurrent ischemia (0.3 vs. 0.5%, P = 0.02) and all-cause mortality (2.2 vs. 2.5%, P = 0.1 [just missing statistical significance]) compared with low-dose (75–100 mg) ASA (4). Although high-dose ASA increased minor bleeds (5.0 vs. 4.4%, P = 0.04), it did not significantly increase major bleeding events. Thus, randomized evidence shows that high-dose ASA in the
U.S. cohort would most likely have reduced mortality in the clopidogrel cohort rather than increased mortality in the ticagrelor
cohort. The aforementioned data clearly indicate the inappropriateness of the statement that “ticagrelor’s benefit is diminished
by high-dose ASA.” Clearly, evidence from CURRENT-OASIS 7 and the FDA Complete Response Review shows that the ticagrelor-ASA
black box warning is not justifiable.

Patients with diabetes in PLATO had a significant reduction in MACE, 30-day all-cause mortality, and 30-day vascular mortality
on high-dose ASA, regardless of treatment arm (HR 0.49 [95% CI 0.34–0.63], P < 0.0001; 0.33 [0.20–0.56], P < 0.0001; and 0.35 [0.22–0.55], P < 0.0001, respectively) (Table 1) (3). Patients with diabetes represent a sizeable cohort in ACS trials and comprised ∼25% of the entire PLATO population (1). It is a well-known phenomenon that patients with diabetes are more likely to be ASA resistant. Moreover, several trials
have clearly indicated that diabetic patients who are ASA resistant on 75–100 mg of ASA can become responders to higher doses
of ASA (5–7). Thus, a reduction in MACE, 30-day all-cause mortality, and 30-day vascular mortality with the use of high-dose ASA in patients
with diabetes from the PLATO trial is consistent with a growing body of evidence. The PLATO diabetes-ASA interaction makes
it highly inappropriate to recommend a black box warning for ASA doses >100 mg with ticagrelor.

Death rates based on potential ticagrelor interactions in the PLATO trial

A limitation of a potential diabetes-ASA interaction is that evidence is based on postrandomization analyses. However, in
the PLATO trial the interaction was highly significant, unlike the ticagrelor-ASA interaction. Furthermore, the diabetic population
represented a much larger (25%) cohort of the PLATO population, whereas the U.S. ticagrelor-ASA interaction represents a much
smaller percentage of PLATO (10%).

Should nondiabetic subjects receive low-dose ASA with ticagrelor? Or should patients with diabetes receive high-dose ASA with
ticagrelor? Answers to these questions are not clear. Another trial, with random assignment of ASA dosages, is urgently needed
to determine the appropriate ASA dose for the patient treated with ticagrelor. In summary, the black box warning for ASA dosages
>100 mg with ticagrelor is inappropriate and unjustifiable, especially for patients with diabetes.

ACKNOWLEDGMENTS

V.L.S. is listed as an inventor for the issued U.S. patent “Treating vascular events with statins by inhibiting PAR-1 and
PAR-4” (7,842,716) assigned to HeartDrug Research and has two pending applications: “Treating cardiac arrhythmias, heart failure,
peripheral vascular disease, and stroke with cyclopentyl-triazolo-pyrimidine or derivative thereof” (U.S.N. 61/253,829), assigned
to HeartDrug, and “Method for treatment of platelet activity with E5555” (U.S.N. 61/080,791), assigned to Eisai and HeartDrug.
V.L.S. received funding for research studies with clopidogrel and E5555, and consultant fees from the manufacturers of both
clopidogrel and ticagrelor. No other potential conflicts of interest relevant to this article were reported.

J.J.D. developed the concept and wrote the manuscript. V.L.S. developed the concept and edited the manuscript.